The overall aim of the proposed studies is to evaluate the relationship between the metabolic and the vascular lesions of diabetes mellitus. Previous studies, both from this laboratory and from the recent NIH cooperative project, have demonstrated that significant quadriceps capillary basement membrance (QCBM) hypertrophy occurs in the prediabetic state, prior to the development of hyperglycemia. The proposed studies will examine QCBM width in a prospective fashion in two groups of prediabetic subjects: 1) the genetically prediabetic patients who have been studied over the past decade in Dallas, Texas; 2) the genetically prediabetic Pima Indian population of New Mexico. By determining the rate of basement membrane hypertrophy in those prediabetic subjects who have already developed thus lesion, and by evaluating the time of appearance of detectable basement membrane thickening in those prediabetic subjects who originally had normal QCBM widths, it should be possible to determine accurately the time relationship between diabetic microangiopathy and the earliest occurrence of hyyperglycemia. In addition, quantitative fluorescein fluorometry will be used to evaluate retinal microangiopathy in these prediabetic subjects. Further, a prospective study of the occurrence and rate of progression of microangiopathy in diabetic children will be pursued, and the relation between the appearance of diabetic retinopathy and QCBM thickening in these subjects will be determined. Finally, microangiopathy will be evaluated in Vacor-induced hyperglycemia, as well as in the hyperglycemia of gestational diabetes, to determine whether QCBM thickening occurs in these putative diabetic states. By determining the state of diabetic microangiopathy, both in genetically prediabetic subjects who have not yet developed hyperglycemia, as well as in individuals who have nongenetic hyperglycemia, it should be possible to arrive at a more definitive answer to the question of whether the microangiopathy of diabetics is the consequence of hyperglycemia or alternatively, whether it represents an independent lesion of the diabetic syndrome.